This invention relates to new 1-(5-arylsulfonyl-phenyl)piperazine and 4-(5-arylsulfonyl-phenyl)piperidine derivatives with 5-HT6 receptor affinity, and associated pharmaceutical compositions, methods for use as therapeutic agents, and methods of preparation thereof.
The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) as a major modulatory neurotransmitter in the brain, are mediated through a number of receptor families termed 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6 receptor may play a role in the pathology and treatment of central nerve system disorders. In particular, 5-HT6 selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson""s disease, Huntington""s disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, migraine, Alzheimer""s disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder. (See for ex. B. L. Roth et al., J. Pharmacol. Exp. Ther.1994, 268, pages 1403-14120, D. R. Sibley et al., Mol. Pharmacol. 1993, 43, 320-327, A. J. Sleight et al, Neurotransmission 1995, 11, 1-5, and A. J. Sleight et al. Serotonin ID Research Alert, 1997, 2 (3), 115-8.
Several arylsulfonyl compounds with 5-HT6 affinity have been disclosed in U.S. Pat. No. 5,990,105 to Bos et al., but it has been surprisingly found that the novel compounds of Formula I possess greater affinity, and therefore would be suitable and highly desirable for the treatment or prevention of central nervous disorders described herein.
This invention relates to compounds comprising Formula (I): 
wherein:
Ar is an optionally substituted aryl group selected from naphthyl or phenyl;
X is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94;
R1 is (C1-C6)alkyl;
R2 and R3 are each independently in each occurrence hydrogen or (C1-C6)alkyl, or R2 and R3 together may form a (C3-C4)alkylene group;
R4 is hydrogen, or R1 and R4 together may form a xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 group; it is understood that R4 and OR1 together with the phenyl to which they are attached would form a benzofuran, a 2,3-dihydrobenzofuran, a chromane, 2,3-dihydro-benzo[1,4]dioxine, or a benzo[1,3]dioxole ring;
or pharmaceutically acceptable salts or solvates thereof.
In another aspect, the invention relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I), or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier.
In another aspect, this invention relates to a method of treatment of a disease in a mammal treatable by administration of compound of Formula (I) having a selective affinity for the 5-HT6 receptor, in particular a method of treatment in a subject having a disease state comprising Alzheimer""s disease, central nervous disorders, such as for example, psychoses, schizophrenia, manic depressions, neurological disorders, Parkinson""s disease, amyotrophic lateral sclerosis and Huntington""s disease. In another aspect, this invention relates to a method of treatment in a subject having a gastrointestinal disease comprising functional bowel disorder.
In a preferred embodiment, the invention further relates to processes for preparing compounds of Formula (I).
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9caxe2x80x9d, xe2x80x9can,xe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise.
xe2x80x9cAlkylxe2x80x9d means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms inclusive, unless otherwise indicated. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
xe2x80x9cLower alkylxe2x80x9d means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d means the radical xe2x80x94Oxe2x80x94R, wherein R is a lower alkyl radical as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
xe2x80x9cArylsulfonylxe2x80x9d means the radical xe2x80x94SO2R, wherein R is an aryl radical as defined herein. Examples of arylsulfonyl radicals include, but are not limited to, benzenesulfonyl, 3-chlorobenzenesulfonyl, naphthalene-2-sulfonyl, naphthalene-1-sulfonyl, and the like.
xe2x80x9cArylxe2x80x9d means the monovalent cyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, aminosulfonyl, sulfonylamino, and/or trifluoromethyl, unless otherwise indicated. Examples of aryl radicals include, but are not limited to, phenyl, naphth-2-yl, naphth-1-yl, fluorophenyl, dichlorophenyl, and the like.
xe2x80x9cLeaving groupxe2x80x9d means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
xe2x80x9cProtective groupxe2x80x9d or xe2x80x9cprotecting groupxe2x80x9d means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen atoms present in the reactants.
xe2x80x9cAmino-protecting groupxe2x80x9d means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptional bondxe2x80x9d means that the bond may or may not be present, and that the description includes single, double, or triple bonds.
xe2x80x9cInert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
xe2x80x9cSolvatesxe2x80x9d means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
xe2x80x9cProdrugxe2x80x9d means a pharmacologically inactive form of a compound which must be metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound. Reference to a compound herein includes prodrug forms of a compound.
xe2x80x9cSubjectxe2x80x9d means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term xe2x80x9csubjectxe2x80x9d does not denote a particular age or sex.
xe2x80x9cTherapeutically effective amountxe2x80x9d means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
xe2x80x9cDisease statexe2x80x9d means any disease, condition, symptom, or indication.
Throughout the application the following abbreviations are used with the following meaning:
Nomenclature
In general, the nomenclature used in this Application is based on AUTONOM(trademark) v.4.0, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.
For example, a compound of Formula (I) wherein Ar is 3-chlorophenyl, R1 is methyl, R2 and R3 are hydrogen and X is xe2x80x94Nxe2x80x94, is named 1-[5-(3-chloro-benzenesufonyl)-2-methoxy-phenyl]-piperazine.
Preferred Compounds
Among compounds of the present invention set forth in the Summary of the Invention, certain compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, are preferred:
Ar is optionally substituted naphthyl or phenyl, and preferably optionally substituted naphthyl wherein the substitutents are independently selected from (C1-C6)alkyl, halogen, haloalkyl, (C1-C6)alkoxy, cyano, nitro, amino, and alkylsulfonyl, or optionally substituted phenyl, wherein the substituents are independently selected from halogen, haloalkyl, (C1-C6)alkoxy, cyano, nitro, and alkylsulfonyl.
X is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94, preferably xe2x80x94Nxe2x80x94.
R1 is (C1-C6)alkyl, preferably methyl.
R2 and R3 are each independently in each occurrence hydrogen or (C1-C6)alkyl, or R2 and R3 together may form a C3-C4 alkylene; preferably R2 and R3 are hydrogen.
R4 is hydrogen or R1 and R4 together may form a xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, or xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 group; preferably R4 is hydrogen.
Exemplary particularly preferred compounds, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, include:
1-[5-(4-chloro-benzenesulfonyl)-2-methoxy-phenyl]-piperazine,
1-[2-methoxy-5-(4-methoxy-benzenesulfonyl)-phenyl]-piperazine,
1-(5-benzenesulfonyl-2-methoxy-phenyl)-piperazine,
1-[2-methoxy-5-(naphthalene-2-sulfonyl)-phenyl]-piperazine,
1-[5-(3-fluoro-benzenesulfonyl)-2-methoxy-phenyl]-piperazine,
1-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazine,
1-[5-(3-chloro-benzenesulfonyl)-2-methoxy-phenyl]-piperazine,
1-[5-(4-chloro-benzenesulfonyl)-2-methoxy-phenyl]-4-methyl-piperazine,
1-[5-(4-fluoro-naphthalene-1-sulfonyl)2-methoxyphenyl]piperazine,
1-[5-(3,4-dichloro-benzenesulfonyl)-2-methoxy-phenyl]-piperazine,
1-[2-methoxy-5-(4-methoxy-naphthalene-1-sulfonyl)phenyl]piperazine,
1-[5-(2,4-dichloro-benzenesulfonyl)-2-methoxy-phenyl]-piperazine, or
4-[5-(4-chloro-benzenesulfonyl)-2-methoxy-phenyl]-piperidine.
Compounds of the present invention may be made by the methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis; Wiley and Sons: New York, 1991, Volumes 1-15; Rodd""s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley and Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about xe2x88x9278xc2x0 C. to about 150xc2x0 C., more preferably from about 0xc2x0 C. to about 125xc2x0 C., and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20xc2x0 C. 
1-(2-Methoxy-phenyl)piperazine or 4-(2-methoxyphenyl) piperidine of general Formula (a) can be protected with an acid resistant protecting group, for example trifluoroacetyl, to afford the protected piperazine or piperidine derivatives of general Formula (b). If the compound of Formula (I) wherein R2 is alkyl is desired, alkylation of the nitrogen can be performed at this point or during Step 5 of this scheme. In Step 2, chlorosulfonation of a compound of general Formula (b) can afford the chlorosulfone of Formula (c), that, as shown in Step 3, after treatment with a Grignard reagent of general Formula ArMgHal, wherein the halide (Hal) is preferably a bromide, can afford the protected compound of Formula (d). In Step 4, deprotection with a strong base such as sodium hydroxyde can afford the piperazine or piperidine compound of general Formula (I) wherein R2 is hydrogen. Steps 3 and 4 can be performed sequentially without isolation of the protected compound of Formula (d). In Step 5, if an alkylated piperazine or piperidine compound is desired, alkylation can be performed at this point by methods well known to the one skilled in the art, such as by the Eschweiler-Clarke procedure, i.e. treatment of the secondary amine with formaldehyde and formic acid, or by reaction with an appropriate alkylhalide in the presence of a base.
Alternatively compound of Formula (b) can be reacted by procedures well known in the art with a compound of general Formula ArSO2Cl to afford the protected compound of Formula (d), which after deprotection can afford a compound of Formula (I), wherein R2 is hydrogen. If the alkylated compound is desired, alkylation can be performed as described herein.
The compounds of the invention have selective 5-HT6 receptor affinity and as such are expected to be useful in the treatment of certain CNS disorders such as Parkinson""s disease, Huntington""s disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorders, migraine, Alzheimer""s disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such functional bowel disorder.
The pharmacology of the compounds of this invention was determined by art recognised procedures. The in vitro techniques for determining the affinities of test compounds at the 5-HT6 receptor in radioligand binding and functional assays are described in Example 13.
The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
In general, compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Examples 6-12.